Health problems resulting from obesity could offset many of the recent health gains achieved by modern medicine, and obesity may replace tobacco as the number one health risk for developed societies. It is estimated that about 97 million adults in the United States are overweight or obese. Approximately 300,000 deaths per year and significant morbidity are directly attributable to obesity, mainly due to heart disease, diabetes, cancer, asthma, sleep apnea, arthritis, reproductive complications and psychological disturbances (Gale et al., J. Nutr. 2004 February; 134(2): 295-8). Obesity results from a positive energy balance, as a consequence of increased ratio of caloric intake to energy expenditure. A lack of physical activity and high fat diets are major factors contributing to this condition. It has been shown that the genetic predisposition of individuals and ethnic groups to obesity also plays a significant role, although the genetic factors leading to obesity are not completely understood.
Increasing degrees of excess body fat and obesity are important predictors of decreased life expectancy. Obesity increases the risk of heart disease, high blood pressure, type II diabetes and other chronic diseases as much as does 20 years of aging (Sturm (2002) Health Affairs 21: 245-253). Additionally, it causes or exacerbates numerous health problems, such as hypertension, elevated plasma insulin concentrations, insulin resistance, dyslepidemias, obstructive sleep apnea, breast, endometrial, prostate and colon cancer, osteoarthritis, arteriosclerosis, abnormal heart rhythms and heart arrhythmias, cholelithiasis, and gallstones (Kopelman (2000) Nature 404: 635-643). Obesity is also associated with an increase in mortality and morbidity from stroke, myocardial infarction, congestive heart failure, coronary heart disease and premature death. Obesity shortens women's lives by seven years and men's lives by six years (Peeters, et al. (2003) Annals of Internal Medicine 138: 24-32).
Over the years, numerous therapeutic modalities have been used for the treatment of obesity, but none have been found to be entirely safe and effective for all patient populations (Bray et al. (1999) Endocrine Reviews 20(6): 805-875). Thyroid extract was reportedly used as early as 1893 (Putnam (1893) Am J Med Sci 106: 125-148). To achieve the effects on body weight, the doses required produced some measure of hyperthyroidism with catabolic consequences on bone, muscle, and the heart. When dinitrophenol was first used in 1933 (Masserman et al. (1934) JAMA 102: 523-525), it was accompanied by neuropathy and cataracts, which led to its discontinuation. The introduction of amphetamine in 1937 (Lesses et al. (1938) N. Engl. J. Med. 218: 119-124) was followed by reports of addiction, a problem that has plagued all of the chemicals that are structurally similar to amphetamine. The use of pills containing amphetamine, digitalis, and diuretics led to several deaths in 1967 and prompted the US Senate to hold hearings. In 1971 aminorex, or aminoxaphen, a new appetite suppressant, was taken off the market in Europe shortly after marketing because of an outbreak of pulmonary hypertension linked to this drug (Kramer et al. (1998) J. Clin. Epidemiol. 51: 361-364). A few years later in 1978, 17 deaths were reported with the use of very-low-calorie diets containing collagen as the principal source of protein (Sours et al. (1981) Am. J. Clin. Nutr. 34: 453-461). Problems with diet clinics led to another set of congressional hearings in 1991, again with little impact except the bankruptcy of several commercial weight loss programs. The final problem has been the valvular heart disease associated with the combined use of fenfluramine and phentermine (Connolly et al. (1997) N. Engl. J. Med. 337:581-588).
Thus, to slow the obesity epidemic, the source needs to be tackled through fundamental research into the mechanisms by which obesity is manifest, and education on the risks and how to prevent it. In order to understand the pathophysiology of obesity it is necessary to investigate the physiology of body weight regulation. Energy intake and body weight are regulated at a very consistent “set-point” by control systems in the hypothalamus. These systems receive feedback from peripheral signals (Schwartz et al. (2000) Nature 404(6778): 661-671). The adipocyte-derived hormone leptin signals the state of fat stores to the brain, inhibiting further food intake and fat accumulation. On the other hand, ghrelin, produced in oxyntic glands in the stomach, serves as an important indicator of energy insufficiency (Zigman et al. (2003) Endocrinology 144(9): 3749-3756).
Ghrelin has been recently identified as an endogenous ligand for the growth hormone secretagogue receptor (GHSR). It is synthesized primarily in the stomach and found in the circulation of healthy humans. Ghrelin is a 28 amino acid peptide hormone with an octanoyl side chain at the third amino acid of its N-terminus (serine 3). This modification is required for the interaction at the GHS receptor and its activity. Ghrelin levels in plasma are influenced by nutritional status and are believed to regulate growth hormone (GH), appetite and fat deposition (Hataya et al. (2001) J. Clin. Endocrinol. Metab. 86: 4552; Nakazato et al. (2001) Nature 409: 194-198; Peino et al. (2000) Eur. J. Endocrinol. 143: R11-R14; Tschop et al. (2000) Nature 407: 908-913; Wren et al. (2001) Diabetes 50: 2540-2547). The observation that ghrelin administration in rats resulted in weight gain as a consequence of changes in energy intake and/or fuel utilization supports such a role. Moreover, systemic ghrelin administration in humans causes sensations of hunger and induces overeating (Wren et al. (2001) J. Clin. Endocrinol. Metab. 86(12): 5992-5995). Based on these findings ghrelin is believed to play a crucial role in the regulation of appetite and body weight, and circulating ghrelin levels serve as an acute as well as a chronic signal of an underfed state. Therefore, ghrelin receptor modulators acting as agonists or antagonists would be able to enhance or reduce appetite and food intake, respectively; these molecules would receive obvious interest for treatment of eating disorders and obesity.
What are needed are alternative modalities for the treatment and prevention of obesity, obesity-related disorders and eating disorders.